Levels of azithromycin and alpha-1 acid glycoprotein in serum in patients with community-acquired pneumonia

Abstract

After an oral dose of 500 mg of azithromycin in patients with community-acquired pneumonia, their serum concentrations ranged between 0.06 and 0.25 mg/liter during the first 12 hours; the calculated percentages of unbound drug varied between 45 and 86%. This study shows that in these patients, the total levels of azithromycin in serum are lower than those expected and that the percentage of bound drug is clinically irrelevant.The pharmacokinetics of azithromycin, one of the new macrolides, are characterized by high tissue concentrations and relatively low serum concentrations. In healthy volunteers, an oral dose of 500 mg of azithromycin leads to maximum serum concentrations of 0.4 to 0.45 mg/liter within 2 to 3 h (10). Azithromycin mainly binds to ␣ 1 -acid glycoprotein (AAG) (10). Concentrations of AAG may increase two-to fourfold during an infection (5), which could result in a decrease of the unbound, i.e., active, fraction of the drug (12). However, although the influence of an infection on the pharmacokinetics of azithromycin has not yet been examined in detail, dosage schedules are based on pharmacokinetics in healthy subjects.The aim of the present study was to establish whether the concentration of azithromycin in patients with community-acquired pneumonia (CAP) corresponds to that found for healthy volunteers. The concentration of AAG was used to calculate the estimated percentage of unbound drug.The Review Committee of the Leiden University Hospital had no objections to this study. Patients with CAP participated in the present study after giving informed consent. Some of the exclusion criteria were the need for intravenous treatment or the presence of disorders which affect the absorption of orally administered drugs. On the 1st day, the patients received 500 mg of azithromycin orally twice, which was followed by 500 mg once daily for the next 4 days. Eight patients, including four females, ranging in age from 32 to 75 years old were enrolled. Streptococcus pneumoniae was detected in four patients (all sensitive to the study drug), and Legionella pneumophila and Mycoplasma pneumoniae were detected each in one patient. In two patients, no pathogen could be found. Only in one patient (subject 5), who had a mycoplasmal pneumonia, did treatment fail.Blood samples were collected immediately before and 3 and 12 h after the first and second doses of azithromycin. Total (bound plus unbound) serum concentrations were determined by an agar well diffusion bioassay (3). The amount of AAG was determined by kinetic nephelometry (Beckman Array Protein System; Beckman Instruments, Inc., Galway, Ireland) in blood samples collected prior to the first dose of azithromycin.Although physical-chemical properties of AAG can change during disease states, values of K d (dissociation constant) and CB max (maximum binding capacity) are found in a relatively small range (6). Therefore, we used the results of a proteinbinding study of azithromycin in healthy volunteers performed by Foulds et al. (2) where CB and CU are the serum ...

Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling

“…Concentrations of an inflammation marker, AAG, are generally believed to increase during an infection, however, quantitative information is limited in patients with viral pneumonia. A 1.7‐fold to 3‐fold increase in AAG levels in patients with community‐acquired pneumonia 28 or SARS‐CoV 29 has been reported. As the above parameters appear to be reasonably consistent with those previously cited for patients with severe renal impairment, 9 they were accounted for in simulations of virtual patients with GFR < 30 mL/min.…”

Systematic review: the bioavailability of orally administered antibiotics during the initial phase of a systemic infection in non-ICU patients

“…Of these, 103 were excluded, and 7 included after full-text screening. In addition, we identified 2 papers by reviewing the reference lists of the included studies, resulting in 9 papers for qualitative analysis [ 21 – 29 ]. (Fig.…”

“…The study characteristics of the 9 included studies are presented in Table 1 . The studies were non-randomized, observational studies [ 21 – 29 ] All studies were performed in hospitalized patients. 6/9 studies reported fever or other signs of acute phase of febrile illness [ 21 , 25 – 29 ].…”

“…The studies were non-randomized, observational studies [ 21 – 29 ] All studies were performed in hospitalized patients. 6/9 studies reported fever or other signs of acute phase of febrile illness [ 21 , 25 – 29 ]. In 3/9 studies, which were the studies that were added after reference screening of the retrieved reviews and the reference lists of the included studies, the febrile state of patients was unclear, which may explain why these records were not captured in our initial search.…”

“…Therefore, we chose to include these studies [ 22 – 24 ]. Four studies originated from The Netherlands [ 21 – 24 ], two from the USA [ 27 , 29 ], one from Canada [ 26 ], one from Egypt [ 25 ] and one from Guatemala [ 28 ]. The pharmacokinetics (PK) of amoxicillin was investigated by two studies [ 22 , 25 ], the PK of azithromycin [ 21 ], ampicillin [ 22 ], clarithromycin [ 26 ] and enoxacin [ 24 ] by one study each and the PK of ciprofloxacin by four studies [ 23 , 27 – 29 ].…”